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Summary MicroRNA (miR)-150 is a developmental regulator of several immune-cell types, but its role in CD8 + T cells is largely unexplored. Here, we show that miR-150 regulates the generation of memory CD8 + T cells. After acute virus infection, miR-150 knockout (KO) mice exhibited an accelerated differentiation of CD8 + T cells into memory cells and improved production of effector cytokines. Additionally, miR-150 KO CD8 + T cells displayed an enhanced recall response and improved protection against infections with another virus and bacteria. We found that forkhead box O1 (Foxo1) and T cell-specific transcription factor 1 (TCF1) are upregulated during the early activation phase in miR-150 KO CD8 + T cells and that miR-150 directly targets and suppresses Foxo1. These results suggest that miR-150-mediated suppression of Foxo1 regulates the balance between effector and memory cell differentiation, which might aid in the development of improved vaccines and T cell therapeutics. [ABSTRACT FROM AUTHOR]

Summary: Reactive oxygen species (ROS) are critical determinants of the fate of hematopoietic stem cells (HSCs) and hematopoiesis. Thioredoxin-interacting protein (TXNIP), which is induced by oxidative stress, is a known regulator of intracellular ROS. Txnip −/− old mice exhibited elevated ROS levels in hematopoietic cells and showed a reduction in hematopoietic cell population. Loss of TXNIP led to a dramatic reduction of mouse survival under oxidative stress. TXNIP directly regulated p53 protein by interfering with p53- mouse double minute 2 (MDM2) interactions and increasing p53 transcriptional activity. Txnip −/− mice showed downregulation of the antioxidant genes induced by p53. Introduction of TXNIP or p53 into Txnip −/− bone marrow cells rescued the HSC frequency and greatly increased survival in mice following oxidative stress. Overall, these data indicate that TXNIP is a regulator of p53 and plays a pivotal role in the maintenance of the hematopoietic cells by regulating intracellular ROS during oxidative stress. [Copyright &y& Elsevier]

Interleukin 10 (IL-10) is a multifunctional cytokine that regulates diverse functions of immune cells. Natural killer (NK) cells express the IL-10 and IL-10 receptor, but little is known about the function of IL-10 on NK cell activation. In this study, we show the expression and role of IL-10 in human NK cells. Among the cytokines tested, IL-15 was the most potent inducer of IL-10, with a maximal peak expression at 5 h after treatment. Furthermore, IL-10 receptor was shown to be expressed in NK cells. IL-10 alone had a significant effect on NK cytotoxicity which additively increased NK cell cytotoxicity in the presence of IL-15. Neutralizing IL-10 with anti-IL-10 antibody suppressed the inductive effect of IL-10 on NK cell cytotoxicity; however, IL-10 had no effect on IFN-γ or TNF-α production or NK cell activatory receptor expression. STAT signals are implicated as a key mediator of IL-10/IL-15 cytotoxicity response. Thus, the effect of IL-10 on NK cells is particularly interesting with regard to the STAT3 signal that was enhanced by IL-10 or IL-15. [ABSTRACT FROM AUTHOR]

Background Intraepithelial lymphocytes (IELs) in the intestines play pivotal roles in maintaining the integrity of the mucosa, regulating immune cells, and protecting against pathogenic invasion. Although several extrinsic factors, such as TGF-β, have been identified to contribute to IEL generation, intrinsic regulatory factors have not been determined fully. Objective Here we investigated the regulation of IEL differentiation and the underlying mechanisms in mice. Methods We analyzed IELs and the expression of molecules associated with IEL differentiation in wild-type control and microRNA (miRNA)-150 knockout mice. Methotrexate was administered to mice lacking miR-150 and control mice. Results miR-150 deficiency reduced the IEL population in the small intestine and increased susceptibility to methotrexate-induced mucositis. Evaluation of expression of IEL differentiation–associated molecules showed that miR-150–deficient IELs exhibited decreased expression of TGF-β receptor (TGF-βR) II, CD103, CD8αα, and Runt-related transcription factor 3 in all the IEL subpopulations. The reduced expression of TGF-βRII in miR-150–deficient IELs was caused by increased expression of c-Myb/miR-20a. Restoration of miR-150 or inhibition of miR-20a recovered the TGF-βRII expression. Conclusion miR-150 is an intrinsic regulator of IEL differentiation through TGF-βRII regulation. miR-150–mediated IEL generation is crucial for maintaining intestinal integrity against anticancer drug–induced mucositis. [ABSTRACT FROM AUTHOR]

The nuclear factor kappa B (NF-κB) pathway is pivotal in controlling survival and apoptosis of cancer cells. Macrophage migration inhibitory factor (MIF), a cytokine that regulates the immune response and tumorigenesis under inflammatory conditions, is upregulated in various tumors. However, the intracellular functions of MIF are unclear. In this study, we found that MIF directly interacted with thioredoxin-interacting protein (TXNIP), a tumor suppressor and known inhibitor of NF-κB activity, and MIF significantly induced NF-κB activation. MIF competed with TXNIP for NF-κB activation, and the intracellular MIF induced NF-κB target genes, including c -IAP2, Bcl-xL, ICAM-1, MMP2 and uPA, by inhibiting the interactions between TXNIP and HDACs or p65. Furthermore, we identified the interaction motifs between MIF and TXNIP via site-directed mutagenesis of their cysteine (Cys) residues. Cys 57 and Cys 81 of MIF and Cys 36 and Cys 120 of TXNIP were responsible for the interaction. MIF reversed the TXNIP-induced suppression of cell proliferation and migration. Overall, we suggest that MIF induces NF-κB activity by counter acting the inhibitory effect of TXNIP on the NF-κB pathway via direct interaction with TXNIP. These findings reveal a novel intracellular function of MIF in the progression of cancer. [ABSTRACT FROM AUTHOR]

• Ginsenoside Rg3 increasd NK cell cytolytic activity. • Ginsenoside Rg3 activated NK cells through the MAPK/ERK signaling pathway. • Ginsenoside Rg3 enhanced the functional maturation of CB-derived NK cells. • Ginsenoside 20(R)-Rg3 was effective at activating NK cells and was activated through the MAPK/ERK signaling pathway. Ginseng is one of the most widely used herbal remedies for various diseases worldwide. Ginsenoside Rg3 (G-Rg3), the main component of ginseng, possesses several pharmacological properties, including anti-inflammatory, anti-tumor, antioxidant, anti-obesity, and immunomodulatory activities. However, the effect of G-Rg3 on natural killer (NK) cells in humans is not fully understood. Here, we investigated the effect of G-Rg3 on NK cell function and differentiation and elucidated the underlying mechanism. G-Rg3 increased NK cell cytotoxicity and simultaneously increased the expression of NK-activating receptors, NKp44, NKp46, and NKp30. Additionally, G-Rg3 increased the mRNA expression of NK cytolytic molecules, granzyme B and perforin. The expression of CD107a, a marker of NK cell degranulation, also increased in G-Rg3–treated NK cells. We therefore proceeded to identify which MAPK signaling pathway was involved in G-Rg3–mediated cytolytic activity. Treatment with G-Rg3 increased the phosphorylation levels of extracellular signal–regulated kinase (ERK), whereas ERK inhibition eliminated G-Rg3–induced NK cell cytotoxicity, suggesting the involvement of the ERK pathway. G-Rg3 did not affect the rate of differentiation of human cord-blood–derived NK cells; however, it increased the functional maturation of differentiated NK cells and promoted their cytotoxicity. The G-Rg3 isomer, 20(R)-Rg3, effectively activated NK cells via the extracellular signal-regulated kinase (ERK) signaling pathway, whereas 20(S)-Rg3 had no effect on NK cell activity. Altogether, the results demonstrated that 20(R)-Rg3 promoted NK cell activity via activation of the MAPK/ERK pathway, suggesting that 20(R)-Rg3 may be used as an activator of NK cell cytotoxicity for the treatment of diverse types of cancers. [ABSTRACT FROM AUTHOR]

Abstract: Natural killer (NK) cells act important roles in innate immunity and adaptive immunity. However, the mechanisms governing NK cell development have not been clearly elucidated. Previous studies have shown that an HMG (high-mobility group) protein, TOX, is important for regulating the differentiation program of developing T cells in mice. In this study, we examined the role of TOX in differentiation of human NK cells. Knockdown of TOX in differentiating cells decreased the NK cell population identified by expression of NK surface markers and receptors. In addition, over-expression of TOX enhanced the differentiation of NK cells which give rise to a population showing effector functions of mature NK cells. Moreover, TOX influenced expression of T-bet (T-box expressed in T cells, also as known as Tbx21) during NK cell development. Overall, these results suggest that TOX is required for IL-15-mediated NK cell differentiation and affected expression of T-bet that plays critical roles in NK differentiation and maturation. [Copyright &y& Elsevier]

Abstract: NK cells play crucial roles in innate immunity and adaptive immunity. The detailed mechanisms, however, governing NK cell development remains unclear. In this study, we report that YC-1 significantly enhances NK cell populations differentiated from human umbilical cord blood hematopoietic stem cells (HSCs). NK cells increased by YC-1 display both phenotypic and functional features of fully mature NK (mNK) cells, but YC-1 does not affect the activation of mNK cells. YC-1 did not affect cGMP production and phosphorylation of STAT-5 which is essential for IL-15R signaling. On the other hand, YC-1 increased p38 MAPK phosphorylation during NK cell differentiation. Furthermore, p38 inhibitor SB203580 inhibited the differentiation of NK cells enhanced by YC-1. Taken together, these data suggest that YC-1 enhances NK cell differentiation through the activation of p38 MAPK which is involved in NK cell differentiation. [Copyright &y& Elsevier]

Adenosine N6-methylation (m6A) is one of the most pervasive mRNA modifications, and yet the physiological significance of m6A removal (demethylation) remains elusive. Here, we report that the m6A demethylase FTO functions as a conserved regulator of motile ciliogenesis. Mechanistically, FTO demethylates and thereby stabilizes the mRNA that encodes the master ciliary transcription factor FOXJ1. Depletion of Fto in Xenopus laevis embryos caused widespread motile cilia defects, and Foxj1 was identified as one of the major phenocritical targets. In primary human airway epithelium, FTO depletion also led to FOXJ1 mRNA destabilization and a severe loss of ciliated cells with an increase of neighboring goblet cells. Consistently, Fto knockout mice showed strong asthma-like phenotypes upon allergen challenge, a result owing to defective ciliated cells in the airway epithelium. Altogether, our study reveals a conserved role of the FTO-FOXJ1 axis in embryonic and homeostatic motile ciliogenesis. [Display omitted] • FTO is required during motile ciliogenesis in a m6A-dependent manner • FTO demethylates and stabilizes the mRNA of transcription factor FOXJ1 • FTO-FOXJ1 axis coordinates the formation of the mammalian airway epithelium • RNA demethylation is critical for motile ciliogenesis in development and homeostasis Kim, Lee et al. examine the physiological significance of RNA demethylation in embryonic development and tissue homeostasis. They show that the m6A demethylase FTO targets the FOXJ1 mRNA to enhance its stability. This posttranscriptional FTO-FOXJ1 axis is essential for proper motile ciliogenesis in frogs, mice, and humans. [ABSTRACT FROM AUTHOR]